Novel Strategy to Prevent Otitis Media Caused by Colonizing Streptococcus pneumoniae

McCullers, Jonathan A.; Karlström, Åsa; Iverson, Amy; Loeffler, Jutta M.; Fischetti, Vincent A.

doi:10.1371/journal.ppat.0030028

Cited by 102 publications

(83 citation statements)

References 14 publications

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“…[12][13][14][15][16][17][18][19][20][21] In relation to bacterial resistance, no strains have yet been identified with resistance to phage lysins. 6,8,19 It has been suggested that these enzymes have evolved to target specific molecules in the host peptidoglycan that are essential for cell viability, making resistance an unlikely event.…”

mentioning

confidence: 99%

The truncated phage lysin CHAP_keliminatesStaphylococcusaureusin the nares of mice

et al. 2010

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mentioning

confidence: 99%

The truncated phage lysin CHAP_keliminatesStaphylococcusaureusin the nares of mice

et al. 2010

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“…In a murine model of nasopharyngeal colonization, a single topical dose of enzyme completely eliminated pneumococci from the mucous membrane. The high effectiveness of Cpl -1 as a topical decolonizing agent was confi rmed in very interesting experiments performed on a novel murine model mimicking the natural development of secondary acute otitis media (AOM) following viral infection in children (McCullers et al 2007 ). In this unique model, a pneumococcal strain engineered to express luciferase was used, which allowed monitoring infection with the use of bioluminescent imaging, was used.…”

Section: Lysins Specifi C To S Pneumoniaementioning

confidence: 99%

Enzybiotics and their Potential Applications in Medicine

Borysowski

Górski

2009

Enzybiotics

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“…In addition, Cpl-1 lysin and Pal amidase encoded by phage Dp-1 act in a synergistic manner in a sepsis mouse model (5); this synergy has also been confirmed in in vitro experiments with Cpl-1 and penicillin or gentamicin (6). Very recently, the creation of a new animal model of otitis media has been reported (7). Using this new mouse model, it has been demonstrated that Cpl-1 could eliminate colonization with S. pneumoniae and prevent the development of otitis media (7).…”

mentioning

confidence: 89%

“…Very recently, the creation of a new animal model of otitis media has been reported (7). Using this new mouse model, it has been demonstrated that Cpl-1 could eliminate colonization with S. pneumoniae and prevent the development of otitis media (7). A paucity of information exists presently on the mechanisms of lysis of pneumococcal cell wall by the phageencoded endolysins at the molecular level.…”

mentioning

confidence: 99%

Elucidation of the Molecular Recognition of Bacterial Cell Wall by Modular Pneumococcal Phage Endolysin CPL-1

Pérez‐Dorado

Campillo

Monterroso

et al. 2007

Journal of Biological Chemistry

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Pneumococcal bacteriophage-encoded lysins are modular proteins that have been shown to act as enzymatic antimicrobial agents (enzybiotics) in treatment of streptococcal infections. The first x-ray crystal structures of the Cpl-1 lysin, encoded by the pneumococcal phage Cp-1, in complex with three bacterial cell wall peptidoglycan (PG) analogues are reported herein. The Cpl-1 structure is folded in two well defined modules, one responsible for anchoring to the pneumococcal cell wall and the other, a catalytic module, that hydrolyzes the PG. Conformational rearrangement of Tyr-127 is a critical event in molecular recognition of a stretch of five saccharide rings of the polymeric peptidoglycan (cell wall). The PG is bound at a stretch of the surface that is defined as the peptidoglycan-binding sites 1 and 2, the juncture of which catalysis takes place. The peptidoglycan-binding site 1 binds to a stretch of three saccharides of the peptidoglycan in a conformation essentially identical to that of the peptidoglycan in solution. In contrast, binding of two peptidoglycan saccharides at the peptidoglycan-binding site 2 introduces a kink into the solution structure of the peptidoglycan, en route to catalytic turnover. These findings provide the first structural evidence on recognition of the peptidoglycan and shed light on the discrete events of cell wall degradation by Cpl-1.Streptococcus pneumoniae is one of the most common and important human pathogens, which causes serious life-threatening diseases such as acute otitis media, pneumonia, sepsis, and meningitis. Pneumococcal infections are associated with high morbidity and mortality, especially among children, the elderly, and the immune-depressed patients. The widespread emergence of antibiotic resistance and the lack of highly effective pneumococcal vaccines against all serotypes of this organism give urgency to elucidation of the molecular processes involved in its pathogenicity (1, 2).The peptidoglycan (PG) 3 scaffold of the bacterial cell wall is a repeating GlcNAc-N-acetylmuramic (MurNAc) disaccharide (GlcNAc-(␤-1,4)-MurNAc) unit having a pentapeptide attached to the D-lactyl moiety of each MurNAc unit. All known pneumococcal bacteriophages encode an amidase or a lysozyme, which hydrolyzes the PG at the final stage of the phage reproductive cycle, leading to bacterial cell lysis. These enzymes, known collectively as endolysins, have been shown to be highly efficient in killing pneumococci in vitro and can eradicate this organism from the upper respiratory tract or from the bloodstream of mice (3, 4) acting as new antimicrobial agents (i.e. enzybiotics). In addition, Cpl-1 lysin and Pal amidase encoded by phage Dp-1 act in a synergistic manner in a sepsis mouse model (5); this synergy has also been confirmed in in vitro experiments with Cpl-1 and penicillin or gentamicin (6). Very recently, the creation of a new animal model of otitis media has been reported (7). Using this new mouse model, it has been demonstrated that Cpl-1 could eliminate colonization with S. p...

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Novel Strategy to Prevent Otitis Media Caused by Colonizing Streptococcus pneumoniae

Cited by 102 publications

References 14 publications

The truncated phage lysin CHAP_keliminatesStaphylococcusaureusin the nares of mice

The truncated phage lysin CHAP_keliminatesStaphylococcusaureusin the nares of mice

Enzybiotics and their Potential Applications in Medicine

Elucidation of the Molecular Recognition of Bacterial Cell Wall by Modular Pneumococcal Phage Endolysin CPL-1

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Novel Strategy to Prevent Otitis Media Caused by Colonizing Streptococcus pneumoniae

Cited by 102 publications

References 14 publications

The truncated phage lysin CHAPkeliminatesStaphylococcusaureusin the nares of mice

The truncated phage lysin CHAPkeliminatesStaphylococcusaureusin the nares of mice

Enzybiotics and their Potential Applications in Medicine

Elucidation of the Molecular Recognition of Bacterial Cell Wall by Modular Pneumococcal Phage Endolysin CPL-1

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Product

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The truncated phage lysin CHAP_keliminatesStaphylococcusaureusin the nares of mice

The truncated phage lysin CHAP_keliminatesStaphylococcusaureusin the nares of mice